In topical administration of medicaments to the eye, a variety of factors can be important, among them comfort, consistency and accuracy of dosage, type and time of any vision interference, ease of administration, and timing of delivery. Prior ophthalmic delivery vehicles have suffered drawbacks in one or more of those areas.
For example, eyedrops in the form of aqueous solutions or suspensions are rapidly washed away by the eye's tear fluid. Ointments or creams blur the vision, and also have comparatively short residence times in the eye. Gelatin lamellae or other films or sheets, ocular inserts and non-aqueous suspensions and emulsions all can cause immediate pain and continuing discomfort and can also interfere with vision.
Highly viscous aqueous gels formed from carboxy vinyl polymers, such as those disclosed in Schoenwald et al. U.S. Pat. Nos. 4,271,143 and 4,407,792, issued June 2, 1981 and Oct. 4, 1983, respectively, are difficult to administer so as to provide consistent, accurate dosages and may be uncomfortable to administer as well. Indeed, above a viscosity of about 30,000 cps, reliable administration in drop form is at best difficult to achieve and at worst impossible. However, at viscosities low enough for reliable administration in drop form, such low viscosities impose an undesirable limitation on delivery efficiency because they render the suspension more amenable to dilution by tears 0f course, higher viscosity suspensions may be employed in an effort to get the suspensions to remain in the eye for a prolonged time period, but such higher viscosities impair ease of administration of accurate drop dosages.
UK Patent Application No. GB 2007091A (Toko) describes carboxy vinyl polymer based gels over a wider viscosity range, namely 1,000 to 100,000 cps. The relatively low viscosity preparations having viscosities of 1,000 to 10,000 are stated to have good flowability and to be amenable to application by drops directly into the mucous membrane around the eyeball. The preparations having viscosities of from 10,000 to 100,000 cps are stated to be amenable to application to the eyelids like conventional ointments. However, in both higher and lower viscosity situations it is stated that the tears liquify the gel. The use of sodium chloride in the preparation is recommended in Toko for sustained efficiency because sodium chloride is said to delay breakdown of the gel when the compositions are applied to the mucous membrane of the eye. However, the sodium chloride is also said to convert the gel to a liquid with a great reduction in viscosity. Therefore, when sodium chloride is added to the composition, increased polymer amounts are recommended to compensate for such viscosity reduction due to the addition of sodium chloride.
Although delaying breakdown of a gel of a given viscosity by using the Toko teachings might have some benefits, it is that given viscosity which will influence whether reliable administration in drop form is achievable or whether ointment-like administration, together with its dosage problems, will be dictated. Whether the alleged sustained efficiency benefit said in Toko to be associated with a sodium chloride additive could even be accomplished at viscosities suitable for drop administration is far from clear from Toko. Nevertheless, even if such a benefit could be obtained with a Toko formulation at a viscosity for administration by drops, the fact that the starting viscosity is at a level low enough to even permit administration by drops is itself limiting on the so-called sustained efficiency. Indeed, as stated in the Toko document, when the preparations are applied, the tears liquify the gel. The sodium chloride merely is said to delay that breakdown.
It would, therefore, be desirable to provide an ophthalmic delivery system which is administrable at a viscosity suitable for reliable drop dosages, but which substantially increases in viscosity after administration. In that way, the drawbacks of either higher or lower viscosity need not be accepted in order to obtain the benefit of the other.
Robinson, U.S. Pat. No. 4,615,697, issued Oct. 7, 1986, discloses a controlled release treatment based on a bioadhesive which is described as a water-swellable, although water insoluble, fibrous, cross-linked carboxyfunctional polymer with a plurality of repeating units in which about at least 80 percent thereof contain at least one carboxy functionality and a crosslinking agent (0.05 to 1.5 percent) that is substantially free of polyalkenyl polyether. It is, first of all, noteworthy that whereas Robinson seeks to exclude the use of polyalkenyl polyether crosslinkers (as are present in Carbapol 934), Toko finds Carbapol 934 especially useful. Moreover, quite apart from that, Robinson neither discloses nor suggests a suspension that is administrable in drop form at a suitable viscosity and which undergoes rapid gelation upon contact with the tears.